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Computational design of a leucine-rich repeat protein with a predefined geometry.

Rämisch, Sebastian LU ; Weininger, Ulrich LU ; Martinsson, Jonas LU ; Akke, Mikael LU and André, Ingemar LU (2014) In Proceedings of the National Academy of Sciences 111(50). p.17875-17880
Abstract
Structure-based protein design offers a possibility of optimizing the overall shape of engineered binding scaffolds to match their targets better. We developed a computational approach for the structure-based design of repeat proteins that allows for adjustment of geometrical features like length, curvature, and helical twist. By combining sequence optimization of existing repeats and de novo design of capping structures, we designed leucine-rich repeats (LRRs) from the ribonuclease inhibitor (RI) family that assemble into structures with a predefined geometry. The repeat proteins were built from self-compatible LRRs that are designed to interact to form highly curved and planar assemblies. We validated the geometrical design approach by... (More)
Structure-based protein design offers a possibility of optimizing the overall shape of engineered binding scaffolds to match their targets better. We developed a computational approach for the structure-based design of repeat proteins that allows for adjustment of geometrical features like length, curvature, and helical twist. By combining sequence optimization of existing repeats and de novo design of capping structures, we designed leucine-rich repeats (LRRs) from the ribonuclease inhibitor (RI) family that assemble into structures with a predefined geometry. The repeat proteins were built from self-compatible LRRs that are designed to interact to form highly curved and planar assemblies. We validated the geometrical design approach by engineering a ring structure constructed from 10 self-compatible repeats. Protein design can also be used to increase our structural understanding of repeat proteins. We use our design constructs to demonstrate that buried Cys play a central role for stability and folding cooperativity in RI-type LRR proteins. The computational procedure presented here may be used to develop repeat proteins with various geometrical shapes for applications where greater control of the interface geometry is desired. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
111
issue
50
pages
17875 - 17880
publisher
National Acad Sciences
external identifiers
  • pmid:25427795
  • wos:000346366500060
  • scopus:84918555133
ISSN
1091-6490
DOI
10.1073/pnas.1413638111
language
English
LU publication?
yes
id
f500c405-c539-4d61-bb75-cf1640222c57 (old id 4815896)
date added to LUP
2014-12-12 15:02:17
date last changed
2017-10-01 03:34:13
@article{f500c405-c539-4d61-bb75-cf1640222c57,
  abstract     = {Structure-based protein design offers a possibility of optimizing the overall shape of engineered binding scaffolds to match their targets better. We developed a computational approach for the structure-based design of repeat proteins that allows for adjustment of geometrical features like length, curvature, and helical twist. By combining sequence optimization of existing repeats and de novo design of capping structures, we designed leucine-rich repeats (LRRs) from the ribonuclease inhibitor (RI) family that assemble into structures with a predefined geometry. The repeat proteins were built from self-compatible LRRs that are designed to interact to form highly curved and planar assemblies. We validated the geometrical design approach by engineering a ring structure constructed from 10 self-compatible repeats. Protein design can also be used to increase our structural understanding of repeat proteins. We use our design constructs to demonstrate that buried Cys play a central role for stability and folding cooperativity in RI-type LRR proteins. The computational procedure presented here may be used to develop repeat proteins with various geometrical shapes for applications where greater control of the interface geometry is desired.},
  author       = {Rämisch, Sebastian and Weininger, Ulrich and Martinsson, Jonas and Akke, Mikael and André, Ingemar},
  issn         = {1091-6490},
  language     = {eng},
  number       = {50},
  pages        = {17875--17880},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Computational design of a leucine-rich repeat protein with a predefined geometry.},
  url          = {http://dx.doi.org/10.1073/pnas.1413638111},
  volume       = {111},
  year         = {2014},
}